Project Summary/Abstract The vast majority of women who have dementia are also post-menopausal. Following menopause, women become more susceptible to risk factors for VCID (vascular contributions to cognitive impairment and dementia). This effect could be mediated by the plummet in gonadal production of estrogen, a hormone that has been shown to be protective against both VCID risk factors and cerebrovascular dysfunction. The effect of estrogen on cognitive impairment in post-menopausal VCID is unknown. Little is known about the mechanisms through which menopause and diminished ovarian estradiol production produce this altered state of VCID risk, leaving opportunities to preserve cognitive function of post-menopausal women underutilized. Post- menopausal estrogen production can still occur through the actions of the enzyme aromatase in a variety of non-gonadal tissues, including the brain. We have previously shown aromatase to be critical for endothelial dependent vasodilation in female mice. Endothelial cells have many vital functions in the brain: forming the blood brain barrier and protecting the highly regulated brain environment from exposure to blood proteins and peripheral immune cells. Blood brain barrier disruption is associated with cognitive impairment in both humans and rodents. The permeability of the blood brain barrier is sensitive to the effects of estrogen and therefore could be influenced by menopause. If blood brain barrier permeability is increased by menopause, it could be a mechanistic link between menopause and cognitive impairment in VCID. In this work, I ask if endothelial and gonadal estradiol production impacts cognitive impairment in VCID, if these effects could be related to changes in blood brain barrier function, and if intraventricular estradiol delivery could have an ameliorative effect on post-menopausal VCID. I will address these questions in three aims. In Aim 1, I will investigate the effects of menopause on VCID in mice by inducing menopause using an ovary-intact method (4-vinylcyclohexene diepoxide). I will use a unilateral carotid artery occlusion surgery to model chronic cerebral hypoperfusion. I will perform behavior testing to assess cognitive deficits and I will compare blood brain barrier permeability and inflammation as candidates to contribute to pathological differences between groups. In Aim 2, I will determine if abolishing endothelial estradiol production by knocking out aromatase specifically in endothelial cells worsens cognitive impairment and pathology in post-menopausal VCID. To do this, I will use our endothelial specific aromatase knock out mice. In Aim 3, I will determine if I can protect against the negative effects of our interventions on cognitive function by specifically delivering estradiol to the intraventricular space in the brain. Funding from this grant will allow me the opportunity to investigate these questions, will facilitate my training and development as a scientist, and will potentially contribute to the prevention and treatment of cognitive impairment in post-menopausal women with VCID.